Incidence of Placebo Adverse Events in Randomized Clinical Trials of Targeted and Immunotherapy Cancer Drugs in the Adjuvant Setting: A Systematic Review and Meta-analysis.
Chacón Matías Rodrigo,Enrico Diego Hernán,Burton Jeannette,Waisberg Federico Daniel,Videla Viviana Marina
JAMA network open
Importance:Several reports have associated the placebo effect with objective response and improvement of a clinical condition in oncology, but only a few studies have analyzed the adverse events (AEs) in the placebo groups of the clinical trials. Objective:To determine the incidence of placebo AEs reported in randomized clinical trials of modern cancer drugs in the adjuvant setting. Data Sources:Based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, a systematic literature search of English-language publications from January 1, 2000, through April 15, 2018, was performed using MEDLINE (PubMed). The following search terms were used to retrieve all trials from the PubMed library: adjuvant, maintenance, consolidation, and placebo, in addition to specific cancer type-related keywords. Study Selection:A double-blind, randomized, placebo-controlled, phase 3 design was mandatory for study inclusion. Only studies enrolling patients who had undergone macroscopically complete resections were included. No other anticancer treatments in addition to placebo were allowed in the control group. Only trials involving a targeted therapy (tyrosine kinase, BRAF, or MEK inhibitors) or immunotherapy-related drugs were included. Trials using chemotherapy, interferon, and endocrine therapy were excluded. Two authors (D.H.E. and F.D.W.) independently reviewed the studies for inclusion. Data Extraction and Synthesis:Data were extracted by investigators, and random-effects meta-analysis was performed to estimate the proportion of grade 3 to 4 placebo AEs in the included studies. Main Outcomes and Measures:Incidence of grade 3 to 4 placebo AEs in the placebo groups. Results:Of 731 studies screened, 10 eligible trials were found including 4 tumor types (melanoma, non-small cell lung cancer, gastrointestinal stromal tumor, and renal cell carcinoma). Overall, 11 143 patients (6270 [56.3%] in the treatment group with mean [SD] age of 55.6 [4.2] years and 4873 patients [43.7%] in the placebo group with mean [SD] age of 55.9 [4.3] years) were included. The mean incidence of any-grade placebo AEs was 85.1% (95% CI, 79.2%-91.0%). The most frequent (mean [SD]) grade 3 to 4 placebo AEs in patients were hypertension (2.8% [2.2%]), fatigue (1.0% [0.9%]), and diarrhea (0.8% [0.6%]). The overall, random-effects pooled incidence of grade 3 to 4 placebo AEs was 18% (95% CI, 15%-21%), with a high level of heterogeneity (I2 = 86%). Frequency of grade 3 to 4 placebo AEs was found to be correlated in the treatment and placebo groups (ρ = 0.7; P = .03). Mean study drug discontinuation owing to placebo AEs was 3.9% (95% CI, 2.7%-5.2%). Conclusions and Relevance:Placebo administration was associated with a substantial incidence of grade 3 to 4 placebo AEs in modern cancer adjuvant trials. This finding should be considered by investigators, sponsors, regulatory authorities, and patient support groups.
Durvalumab as third-line or later treatment for advanced non-small-cell lung cancer (ATLANTIC): an open-label, single-arm, phase 2 study.
Garassino Marina Chiara,Cho Byoung-Chul,Kim Joo-Hang,Mazières Julien,Vansteenkiste Johan,Lena Hervé,Corral Jaime Jesus,Gray Jhanelle E,Powderly John,Chouaid Christos,Bidoli Paolo,Wheatley-Price Paul,Park Keunchil,Soo Ross A,Huang Yifan,Wadsworth Catherine,Dennis Phillip A,Rizvi Naiyer A,
The Lancet. Oncology
BACKGROUND:Immune checkpoint inhibitors are a new standard of care for patients with advanced non-small-cell lung cancer (NSCLC) without EGFR tyrosine kinase or anaplastic lymphoma kinase (ALK) genetic aberrations (EGFR-/ALK-), but clinical benefit in patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) has not been shown. We assessed the effect of durvalumab (anti-PD-L1) treatment in three cohorts of patients with NSCLC defined by EGFR/ALK status and tumour expression of PD-L1. METHODS:ATLANTIC is a phase 2, open-label, single-arm trial at 139 study centres in Asia, Europe, and North America. Eligible patients had advanced NSCLC with disease progression following at least two previous systemic regimens, including platinum-based chemotherapy (and tyrosine kinase inhibitor therapy if indicated); were aged 18 years or older; had a WHO performance status score of 0 or 1; and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Key exclusion criteria included mixed small-cell lung cancer and NSCLC histology; previous exposure to any anti-PD-1 or anti-PD-L1 antibody; and any previous grade 3 or worse immune-related adverse event while receiving any immunotherapy agent. Patients in cohort 1 had EGFR+/ALK+ NSCLC with at least 25%, or less than 25%, of tumour cells with PD-L1 expression. Patients in cohorts 2 and 3 had EGFR-/ALK- NSCLC; cohort 2 included patients with at least 25%, or less than 25%, of tumour cells with PD-L1 expression, and cohort 3 included patients with at least 90% of tumour cells with PD-L1 expression. Patients received durvalumab (10 mg/kg) every 2 weeks, via intravenous infusion, for up to 12 months. Retreatment was allowed for patients who benefited but then progressed after completing 12 months. The primary endpoint was the proportion of patients with increased tumour expression of PD-L1 (defined as ≥25% of tumour cells in cohorts 1 and 2, and ≥90% of tumour cells in cohort 3) who achieved an objective response, assessed in patients who were evaluable for response per independent central review according to RECIST version 1.1. Safety was assessed in all patients who received at least one dose of durvalumab and for whom any post-dose data were available. The trial is ongoing, but is no longer open to accrual, and is registered with ClinicalTrials.gov, number NCT02087423. FINDINGS:Between Feb 25, 2014, and Dec 28, 2015, 444 patients were enrolled and received durvalumab: 111 in cohort 1, 265 in cohort 2, and 68 in cohort 3. Among patients with at least 25% of tumour cells expressing PD-L1 who were evaluable for objective response per independent central review, an objective response was achieved in 9 (12·2%, 95% CI 5·7-21·8) of 74 patients in cohort 1 and 24 (16·4%, 10·8-23·5) of 146 patients in cohort 2. In cohort 3, 21 (30·9%, 20·2-43·3) of 68 patients achieved an objective response. Grade 3 or 4 treatment-related adverse events occurred in 40 (9%) of 444 patients overall: six (5%) of 111 patients in cohort 1, 22 (8%) of 265 in cohort 2, and 12 (18%) of 68 in cohort 3. The most common treatment-related grade 3 or 4 adverse events were pneumonitis (four patients [1%]), elevated gamma-glutamyltransferase (four [1%]), diarrhoea (three [1%]), infusion-related reaction (three [1%]), elevated aspartate aminotransferase (two [<1%]), elevated transaminases (two [<1%]), vomiting (two [<1%]), and fatigue (two [<1%]). Treatment-related serious adverse events occurred in 27 (6%) of 444 patients overall: five (5%) of 111 patients in cohort 1, 14 (5%) of 265 in cohort 2, and eight (12%) of 68 in cohort 3. The most common serious adverse events overall were pneumonitis (five patients [1%]), fatigue (three [1%]), and infusion-related reaction (three [1%]). Immune-mediated events were manageable with standard treatment guidelines. INTERPRETATION:In patients with advanced and heavily pretreated NSCLC, the clinical activity and safety profile of durvalumab was consistent with that of other anti-PD-1 and anti-PD-L1 agents. Responses were recorded in all cohorts; the proportion of patients with EGFR-/ALK- NSCLC (cohorts 2 and 3) achieving a response was higher than the proportion with EGFR+/ALK+ NSCLC (cohort 1) achieving a response. The clinical activity of durvalumab in patients with EGFR+ NSCLC with ≥25% of tumour cells expressing PD-L1 was encouraging, and further investigation of durvalumab in patients with EGFR+/ALK+ NSCLC is warranted. FUNDING:AstraZeneca.
Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial.
Quoix Elisabeth,Ramlau Rodryg,Westeel Virginie,Papai Zsolt,Madroszyk Anne,Riviere Alain,Koralewski Piotr,Breton Jean-Luc,Stoelben Erich,Braun Denis,Debieuvre Didier,Lena Hervé,Buyse Marc,Chenard Marie-Pierre,Acres Bruce,Lacoste Gisèle,Bastien Bérangère,Tavernaro Annette,Bizouarne Nadine,Bonnefoy Jean-Yves,Limacher Jean-Marc
The Lancet. Oncology
BACKGROUND:Chemotherapy is the standard of care for advanced stages of non-small-cell lung cancer (NSCLC). TG4010 is a targeted immunotherapy based on a poxvirus (modified vaccinia virus Ankara) that codes for MUC1 tumour-associated antigen and interleukin 2. This study assessed TG4010 in combination with first-line chemotherapy in advanced NSCLC. METHODS:148 patients with advanced (stage IIIB [wet] or IV) NSCLC expressing MUC1 by immunohistochemistry, and with performance status 0 or 1, were enrolled in parallel groups in this open-label, phase 2B study. 74 patients were allocated to the combination therapy group, and received TG4010 (10(8) plaque forming units) plus cisplatin (75 mg/m(2) on day 1) and gemcitabine (1250 mg/m(2) on days 1 and 8) repeated every 3 weeks for up to six cycles. 74 patients allocated to the control group received the same chemotherapy alone. Patients were allocated using a dynamic minimisation procedure stratified by centre, performance status, and disease stage. The primary endpoint was 6-month progression-free survival (PFS), with a target rate of 40% or higher in the experimental group. Analyses were done on an intention-to-treat basis. This study is completed and is registered with ClinicalTrials.gov, number NCT00415818. FINDINGS:6-month PFS was 43·2% (32 of 74; 95% CI 33·4-53·5) in the TG4010 plus chemotherapy group, and 35·1% (26 of 74; 25·9-45·3) in the chemotherapy alone group. Fever, abdominal pain, and injection-site pain of any grade according to National Cancer Institute Common Toxicity Criteria were more common in the TG4010 group than in the chemotherapy alone group: 17 of 73 patients (23·3%) versus six of 72 (8·3%), 12 (16·4%) versus two (2·8%), and four (5·5%) versus zero (0%), respectively. The most common grade 3-4 adverse events were neutropenia (33 [45·2%] of patients in the TG4010 plus chemotherapy group vs 31 [43·1%] in the chemotherapy alone group) and fatigue (18 [24·7%] vs 13 [18·1%]); the only grade 3-4 events that differed significantly between groups were anorexia (three [4·1%] vs 10 [13·9%]) and pleural effusion (none vs four [5·6%]). 38 of 73 patients (52·1%) in the TG4010 plus chemotherapy group and 34 of 72 (47·2%) in the chemotherapy alone group had at least one serious adverse event. INTERPRETATION:This phase 2B study suggests that TG4010 enhances the effect of chemotherapy in advanced NSCLC. A confirmatory phase 2B-3 trial has been initiated. FUNDING:Transgene SA, Advanced Diagnostics for New Therapeutic Approaches (ADNA)/OSEO.
Relapse of aseptic meningitis induced by ipilimumab and nivolumab therapy for metastatic renal cell carcinoma: A case report.
Takamatsu Dai,Furubayashi Nobuki,Negishi Takahito,Ieiri Kosuke,Inoue Tomohiro,Tsukino Keiji,Nakamura Motonobu
Molecular and clinical oncology
The combined immunotherapy of nivolumab and ipilimumab causes a variety of autoimmune-related adverse events (irAEs). The current report details a 70-year-old woman with clear cell renal cell carcinoma metastasis in the lung. Two weeks after two courses of treatment, the patient complained of headache, dizziness and nausea. Cerebrospinal fluid (CSF) analysis revealed an elevated protein level of 195 mg/dl and a significantly elevated white blood cell (WBC) count of 830/mm (lymphocytes, 825/mm; neutrophils, 5/mm). The results excluded malignancy and infection. The patient was diagnosed with aseptic meningitis and was administered intravenous prednisolone (1 mg/kg/day). On the 49th day of the 2nd course of treatment, no recurrence of clinical symptoms was exhibited during maintenance oral steroid treatment (prednisolone 10 mg/day) and CSF analysis revealed that the WBC count had dropped to 44/mm (lymphocytes only). Therefore, the 3rd course of treatment was readministered the next day. After two weeks, the patients again complained of nausea, anorexia and fatigue. CSF analysis demonstrated that the WBC count was not increased from the result obtained previously. However, brain MRI scans revealed the mild diffuse enlargement of the pituitary and endocrine system tests revealed reduced adrenocorticotropic hormone (ACTH; 2.0 pg/ml) and cortisol (1.12 µg/dl) levels. The patient was diagnosed with isolated ACTH deficiency and oral hydrocortisone was administered after prednisolone cessation. On the 25th day of the 3rd course of treatment, the patient complained of headache and anorexia. CSF examination revealed that the WBC count had increased a second time (53/mm; lymphocytes only) and laboratory data revealed hepatic dysfunction. The patient was then diagnosed with relapse of aseptic meningitis and liver dysfunction. While continuing oral hydrocortisone treatment, the administration of intravenous prednisolone was started. The observed liver dysfunction and aseptic meningitis gradually improved. The current report may be useful for avoiding delays in the diagnosis and treatment of this life-threatening and uncommon irAE, in which CSF examinations are useful for diagnosis and management.
Isolated ACTH deficiency during single-agent pembrolizumab for squamous cell lung carcinoma: a case report.
Tanaka Sho,Kushimoto Masaru,Nishizawa Tsukasa,Takubo Masahiro,Mitsuke Kazutaka,Ikeda Jin,Fujishiro Midori,Ogawa Katsuhiko,Tsujino Ichiro,Suzuki Yutaka,Abe Masanori
Clinical diabetes and endocrinology
Background:The programmed cell death 1 (PD-1) inhibitor pembrolizumab is a promising agent for treatment of several different malignancies, but as with all immunotherapy there is a potential risk of immune-related adverse events. Adrenocorticotropic hormone (ACTH) deficiency and hypophysitis have been reported in patients treated with a different PD-1 inhibitor, nivolumab. However, clinical characteristics of these side effects associated with pembrolizumab have yet to be described in detail. Case presentation:An 85-year-old Japanese woman was diagnosed with advanced squamous cell lung cancer. The patient was treated with 200 mg pembrolizumab every three weeks as first-line therapy. Routine examination including thyroid function, complete blood count, serum cortisol and sodium levels before each pembrolizumab infusion had shown no significant changes up to the eighth cycle. However, 8 days after the eighth cycle of single-agent pembrolizumab, she presented with rapidly worsening general fatigue and appetite loss over two days. Laboratory data revealed a low serum cortisol level (0.92 μg/dL) with inappropriately low ACTH (8.3 pg/mL), hyponatremia (122 mmol/L) and hypoglycemia (68 mg/dL). Standard-dose short ACTH testing showed an unsatisfactory cortisol response, indicating adrenal insufficiency. Pituitary magnetic resonance imaging showed diffuse substantial gadolinium enhancement, T2 hyperintensity, loss of pituitary bright spot, but no pituitary enlargement. Serum cortisol and ACTH levels were low throughout the day, and urinary free cortisol excretion fell below the lower normal limit. There was no ACTH and cortisol response in the corticotropin-releasing hormone test, despite significant responses of other anterior pituitary hormones to their corresponding challenge tests. Thus, isolated ACTH deficiency was diagnosed, and hypophysitis was suspected as the etiology. After administration of 15 mg/day hydrocortisone, the patient's debilitation, hyponatremia, and hypoglycemia swiftly disappeared. Conclusion:This is a case of isolated ACTH deficiency possibly due to hypophysitis in a patient with advanced lung cancer, in whom recent routine examinations had shown unremarkable results. We therefore conclude that isolated ACTH deficiency can suddenly arise during pembrolizumab monotherapy, albeit probably only rarely. Caution should be exercised to make sure that adrenal insufficiency is recognized immediately in order to achieve swift recovery by steroid replacement.
[Analysis of Advanced or Postoperative Recurrent Non-small Lung Cancer Cases Treated with Nivolumab].
Ichiki Yoshinobu,Iwanami Takashi,Kakizoe Kesei,Hamatsu Takayuki,Suehiro Taketoshi,Yoneda Kazue,Tanaka Fumihiro,Sugimachi Keizo
Journal of UOEH
Recent developments in cancer immunotherapy are remarkable. Many reports have described the clinical effects of immune checkpoint inhibitors (ICIs), supporting their utility as a promising therapy that will achieve prominent effects even in patients resistant to cytotoxic anticancer drugs or gene-targeting therapy. ICIs may also prolong overall survival. We analyzed 10 cases of advanced lung cancer targeted with nivolumab, which is one of ICIs in our hospital and reviewed the literature regarding ICIs. We retrospectively analyzed 10 cases that consisted of 6 males and 4 females, which comprised 7 adenocarcinomas, 2 squamous cell carcinomas and one pleomorphic carcinoma. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase mutations were negative in all the adenocarcinoma cases. The 10 analyzed cases included 9 inoperable cases and 1 postoperative recurrent case, 8 second-line cases, a third-line case, and a fourth-line case. The average frequency of administrations of nivolumab was 7.4 times. The survival rate was calculated by using the Kaplan-Meier method. The clinical responses to nivolumab were partial response in 2 cases, stable disease in 4 cases, and progressive disease in 4 cases. In the 10 cases, the response rate and disease control rate were 20% and 60%, respectively. The median progression-free survival time and median survival time were 115 days and 126 days, respectively. We observed 2 cases of dermatitis and one each of pyrexia, general fatigue and drug-induced pneumonia as adverse events (AEs). One of these AEs was severe (Stevens-Johnson syndrome grade 4) but could be treated by steroid pulse therapy, steroid ointment and instillation. Among the 10 examined cases of advanced lung cancer treated with ICIs at our hospital, ICIs proved effective in 2 cases. However, we also experienced a case with Stevens-Johnson syndrome grade 4 as a severe AE. These findings suggest that while ICIs may be effective in treating patients, candidates for ICIs must be carefully selected and cautiously observed.
Nivolumab Induced Adrenal Insufficiency: Rare Side-effect of a New Anti-cancer Therapy - Immune-checkpoint Inhibitors.
Rai Maitreyee,Go Mylene
Immune-checkpoint inhibitors are immuno-modulatory antibodies used in patients with advanced cancers like melanoma, renal cell carcinoma, non-small cell lung cancer, etc. They are associated with a wide array of side effects, commonly known as immune-related adverse events (irAEs), affecting dermatological, gastrointestinal, hepatic, endocrine, and other systems. We present a case of nivolumab-induced adrenal insufficiency in a patient presenting with refractory hypotension. The patient is a 77-year-old caucasian male with metastatic renal cell carcinoma (RCC) on nivolumab therapy, presented to his primary doctor for symptoms of fatigue, weakness, loss of appetite, and dizziness. His initial blood pressure (BP) was noted to be 78/44 mmHg, so he was referred to the emergency department. He received several liters of intravenous (IV) fluid boluses; however, BP consistently stayed in 90s systolic and 40-50 diastolic. The lab investigations showed a low sodium level at 128 mmol/L, blood urea nitrogen (BUN) elevated at 37 mg/dL, creatinine elevated at 2.7 mg/dL. A morning cortisol level was checked; it came back low at 1.3 mcg/dL. Further testing with the cosyntropin stimulation test revealed low basal cortisol of 1 mcg/dL and only a mild increase to 10.20 mcg/dL after the cosyntropin administration. Adrenocorticotrophic hormone (ACTH) was checked that came out to be low <5pg/mL, favoring a diagnosis of secondary adrenal insufficiency likely due to hypophysitis. In the meantime, the patient was started on hydrocortisone, which improved his blood pressure significantly. He was eventually weaned from IV hydrocortisone to p.o. hydrocortisone. The nivolumab was discontinued, and oncology decided on giving a nivolumab re-challenge once the patient was stabilized. Our patient presented with common manifestations of adrenal insufficiency like fatigue, hypotension, and hyponatremia, which is one of the rare irAEs occurring in <1% of the patients. These are non-specific manifestations and can be easily overlooked if adverse events of immunotherapy are not suspected. Even though rare, adrenal insufficiency is a life-threatening side-effect of immune checkpoint inhibitor drugs that need to be recognized immediately and managed with intravenous glucocorticoids.
FIT: Functional and imaging testing for patients with metastatic cancer.
Roeland Eric J,Phull H,Hagmann C,Sera C,Dullea A D,El-Jawahri A,Nelson S,Gallivan A,Ma J D,Nipp R D,Baracos V E
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer
BACKGROUND:Selecting study endpoints in prospective cancer cachexia trials remains poorly defined. The aim of this study was to further evaluate associations in changes in weight, body composition, functional outcomes, and patient-reported outcomes (PROs) in patients with metastatic cancer. METHODS:We completed a 2-year (2016-2018) observational study in patients with metastatic solid cancer and ECOG performance status 0 to 2 while receiving chemotherapy and/or immunotherapy. We completed assessments at study enrollment and 3 months from enrollment. We analyzed longitudinal changes in weight and body composition using validated methods. Functional assessments included the 6-Min Walk Test, Timed Up and Go Test, and Short Physical Performance Battery. PROs included the Functional Assessment of Anorexia/Cachexia Therapy and Functional Assessment of Cancer Therapy Fatigue. We analyzed changes in body composition and functional assessment using paired t tests. Additionally, we utilized linear regression models to assess relationships between changes in body composition and function outcomes and PROs, adjusting for age and sex. RESULTS:A total of 57 patients completed baseline assessments, but 19 patients did not complete 3-month assessments (5 died, 1 hospice, 13 withdrew). Of the 38 patients with complete data, the mean age was 61.8 years and 47% were female. Metastatic cancer types included 71% gastrointestinal, 13% lung, and 8% gynecologic. Half received chemotherapy, 16% immunotherapy, and 34% a combination. From enrollment to 3 months, we did not observe a change in weight or skeletal muscle but did find an increase in total adipose tissue (16.9 ± 52.4 cm, 95% CI - 33.79-0.63; p = 0.059; ~ 1.5 pounds). We did not observe any association with changes in weight with any functional outcomes or PROs. However, greater losses in skeletal muscle were associated with greater declines in physical function (6-Min Walk Test [B = 0.04, p = 0.01], Short Physical Performance Battery [B = 2.44, p < 0.01]). CONCLUSIONS:Patients with metastatic cancer receiving cancer-directed therapy may not experience a change in body weight. However, we found an association between losses in skeletal muscle and greater declines in physical function. Therefore, when selecting study endpoints, prospective cancer cachexia studies may consider selecting changes in body composition over weight.
A phase II study of dacetuzumab (SGN-40) in patients with relapsed diffuse large B-cell lymphoma (DLBCL) and correlative analyses of patient-specific factors.
de Vos Sven,Forero-Torres Andres,Ansell Stephen M,Kahl Brad,Cheson Bruce D,Bartlett Nancy L,Furman Richard R,Winter Jane N,Kaplan Henry,Timmerman John,Whiting Nancy C,Drachman Jonathan G,Advani Ranjana
Journal of hematology & oncology
BACKGROUND:Patients with DLBCL who are ineligible for or have relapsed after aggressive salvage chemotherapy have a poor prognosis. CD40 is expressed on multiple B-cell neoplasms including DLBCL and is a potential target for immunotherapy. Dacetuzumab (SGN-40), a non-blocking, partial agonist, humanized IgG1, anti-CD40 monoclonal antibody, has previously demonstrated anti-lymphoma activity in a phase I study. METHODS:A phase II study was undertaken to evaluate the rate and duration of objective responses and safety of single-agent dacetuzumab in relapsed DLBCL. Forty-six adult patients with relapsed/refractory DLBCL received up to 12 cycles of intravenous dacetuzumab using intrapatient dose-escalation to a target dose of 8 mg/kg/week in an initial 5-week cycle, followed by 4-week cycles of 8 mg/kg/week. Study endpoints included rate and duration of objective responses, safety, survival, pharmacokinetics, immunogenicity, and exploratory correlative studies. RESULTS:Overall response rate was 9% and disease control rate (complete remission + partial remission + stable disease) was 37%. Common non-hematologic adverse events (AEs) included fatigue, headache, chills, fever, and nausea. The most frequent Grade 3-4 non-hematologic AE was deep venous thrombosis (3 patients). Grade 3-4 lymphopenia (41%), neutropenia (13%), or thrombocytopenia (19%) occurred without associated infection or bleeding. Reversible ocular events, including conjunctivitis and ocular hyperemia, occurred in 8 patients (17%). Patient-specific factors, including Fc-gamma-RIIIa polymorphism, did not appear to correlate with antitumor activity. CONCLUSIONS:Single-agent dacetuzumab has modest activity and manageable toxicity in unselected patients with relapsed DLBCL. Combination regimens and robust methods of patient selection may be necessary for further development. TRIAL REGISTRATION:ClinicalTrials.gov identifier NCT00435916.
Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions.
King-Kallimanis Bellinda L,Howie Lynn J,Roydhouse Jessica K,Singh Harpreet,Theoret Marc R,Blumenthal Gideon M,Kluetz Paul G
Clinical trials (London, England)
BACKGROUND:Patient-reported outcome measures can be used to capture the patient's experience with disease and treatment. Immunotherapy agents including the anti-programmed death receptor-1/programmed death-ligand-1 inhibitor therapies have unique symptomatic side effects and patient-reported outcome data can help to characterize the benefits and burdens associated with therapy. METHODS:We reviewed registration trials in the Food and Drug Administration database for five anti-programmed death receptor-1/programmed death-ligand-1 inhibitor therapies to characterize trial design and patient-reported outcome assessment strategy (cutoff 31 December 2017). We evaluated the patient-reported outcome measurement coverage of eight key symptoms related to adverse events reported in immunotherapy agent product labels (fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritus, and fever). RESULTS:There were a total of 28 trials across seven disease types and one tumor agnostic indication reviewed, of which 17 were randomized and 25 were open label. Of the 28 trials, 21 contained patient-reported outcome measures and all 21 used >1 instrument. The most common instruments were the EuroQol five dimension (N = 19), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (N = 17). Disease-specific patient-reported outcome tools were included in nine trials (six lung, one head and neck, one melanoma and one renal cell). No trial used a patient-reported outcome strategy assessing all eight selected adverse events. CONCLUSION:Collection of patient-reported outcome data in anti-programmed death receptor-1/programmed death-ligand-1 inhibitor trials were variable and did not consistently assess important symptomatic adverse events. Use of a patient-reported outcome instrument with well-defined functional scales supplemented by item libraries to incorporate relevant symptomatic adverse events may allow for improved understanding of the patient experience while receiving therapy. These data, along with other clinical data such as hospitalizations and supportive care medication use can help inform the benefit-risk assessment for regulatory purposes.
Hepatotoxicity of immune check point inhibitors: Approach and management.
Lleo Ana,Rimassa Lorenza,Colombo Massimo
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
Therapeutic reversal of immune tolerance following immune checkpoint inhibitors (ICPI) administration, has proven effective in prolonging survival of patients with a variety of solid and liquid tumors, often however at the expenses of discrete toxicities known as immune-related adverse events (AEs). Such reactions result from activation of the immune system and often present with generalized symptoms including fatigue or fever and, in some patients, may cause organ-specific damage. Skin, gut, endocrine, lung and musculoskeletal are the most frequent targets of ICPI toxicity whereas, cardiovascular, hematologic, renal, neurologic and ophthalmologic AEs occur much less frequently. While the majority of AEs are mild to moderate, serious, occasionally life-threatening reactions have been reported, including severe colitis, pneumonitis, encephalitis, toxic epidermal necrolysis, myocarditis, and diabetic ketoacidosis, with a death toll of 2%. Hepatocellular carcinoma (HCC) is becoming an attractive area for immunotherapy. Owing to the fact that the association of HCC with cirrhosis may jeopardize tolerability of ICPI therapy, attention has been paid to identifying, preventing, and treating the AEs associated with ICPI, with a focus on liver safety. Though in most studies AEs resolved with interruption of treatment and short course of steroids, identification of predictive biomarkers of response might help sparing patients from potentially life-threatening toxicity in the absence of clinical benefit.
Immunotherapy Associated Pulmonary Toxicity: Biology Behind Clinical and Radiological Features.
Porcu Michele,De Silva Pushpamali,Solinas Cinzia,Battaglia Angelo,Schena Marina,Scartozzi Mario,Bron Dominique,Suri Jasjit S,Willard-Gallo Karen,Sangiolo Dario,Saba Luca
The broader use of immune checkpoint blockade in clinical routine challenges clinicians in the diagnosis and management of side effects which are caused by inflammation generated by the activation of the immune response. Nearly all organs can be affected by immune-related toxicities. However, the most frequently reported are: fatigue, rash, pruritus, diarrhea, nausea/vomiting, arthralgia, decreased appetite and abdominal pain. Although these adverse events are usually mild, reversible and not frequent, an early diagnosis is crucial. Immune-related pulmonary toxicity was most frequently observed in trials of lung cancer and of melanoma patients treated with the combination of the anti-cytotoxic T lymphocyte antigen (CTLA)-4 and the anti-programmed cell death-1 (PD-1) antibodies. The most frequent immune-related adverse event in the lung is represented by pneumonitis due to the development of infiltrates in the interstitium and in the alveoli. Clinical symptoms and radiological patterns are the key elements to be considered for an early diagnosis, rendering the differential diagnosis crucial. Diagnosis of immune-related pneumonitis may imply the temporary or definitive suspension of immunotherapy, along with the start of immuno-suppressive treatments. The aim of this work is to summarize the biological bases, clinical and radiological findings of lung toxicity under immune checkpoint blockade, underlining the importance of multidisciplinary teams for an optimal early diagnosis of this side effect, with the aim to reach an improved patient care.
Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review.
Fritz Heidi,Kennedy Deborah A,Ishii Mami,Fergusson Dean,Fernandes Rochelle,Cooley Kieran,Seely Dugald
Integrative cancer therapies
BACKGROUND:Polysaccharide K, also known as PSK or Krestin, is derived from the Coriolus versicolor mushroom and is widely used in Japan as an adjuvant immunotherapy for a variety of cancer including lung cancer. Despite reported benefits, there has been no English language synthesis of PSK for lung cancer. To address this knowledge gap, we conducted a systematic review of PSK for the treatment of lung cancer. METHODS:We searched PubMed, EMBASE, CINAHL, the Cochrane Library, AltHealth Watch, and the Library of Science and Technology from inception to August 2014 for clinical and preclinical evidence pertaining to the safety and efficacy of PSK or other Coriolus versicolor extracts for lung cancer. RESULTS:Thirty-one reports of 28 studies were included for full review and analysis. Six studies were randomized controlled trials, 5 were nonrandomized controlled trials, and 17 were preclinical studies. Nine of the reports were Japanese language publications. Fifteen of 17 preclinical studies supported anticancer effects for PSK through immunomodulation and potentiation of immune surveillance, as well as through direct tumor inhibiting actions in vivo that resulted in reduced tumor growth and antimetastatic effects. Nonrandomized controlled trials showed improvement of various survival measures including median survival and 1-, 2-, and 5-year survival. Randomized controlled trials showed benefits on a range of endpoints, including immune parameters and hematological function, performance status and body weight, tumor-related symptoms such as fatigue and anorexia, as well as survival. Although there were conflicting results for impact on some of the tumor-related symptoms and median survival, overall most randomized controlled trials supported a positive impact for PSK on these endpoints. PSK was safely administered following and in conjunction with standard radiation and chemotherapy. CONCLUSIONS:PSK may improve immune function, reduce tumor-associated symptoms, and extend survival in lung cancer patients. Larger, more rigorous randomized controlled trials for PSK in lung cancer patients are warranted.
Patient-Reported Outcomes From Patients Receiving Immunotherapy or Chemoimmunotherapy for Metastatic Non-Small-Cell Lung Cancer in Clinical Practice.
Steffen McLouth Laurie E,Lycan Thomas W,Levine Beverly J,Gabbard Jennifer,Ruiz Jimmy,Farris Michael,Grant Stefan C,Pajewski Nicholas M,Weaver Kathryn E,Petty W Jeffrey
Clinical lung cancer
INTRODUCTION:Immunotherapy and chemoimmunotherapy clinical trials for metastatic non-small-cell lung cancer (mNSCLC) have generally excluded patients with poor performance status (PS) and have utilized patient-reported measures that could miss some symptoms associated with immunotherapy. The goals of this study were to describe quality of life and symptom burden among mNSCLC patients receiving immunotherapy in clinical practice, and to examine burden by Eastern Cooperative Oncology Group performance status (ECOG PS) and age. PATIENTS AND METHODS:Between 2017 and 2018, mNSCLC patients receiving immuno/chemoimmunotherapy at an academic medical center completed the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC-QLQ-C30) and the National Cancer Institute Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Univariate and bivariate analyses described EORTC-QLQ-C30 subscales and the proportion reporting at least moderate PRO-CTCAE symptoms, and compared scores by ECOG PS (0/1 vs. 2/3) and age (< 70 vs. ≥ 70 years). RESULTS:Sixty patients (60% female; 75% < 70 years old; 68% ECOG PS 0/1; 57% receiving single-agent immunotherapy) participated. The mean EORTC-QLQ-C30 global health score was 62.6; EORTC symptoms were highest for fatigue, insomnia, dyspnea, and financial concerns (all > 30). Global health and pain were worse in ECOG PS 2/3 patients. For PRO-CTCAE, 20% to 40% reported at least moderate gastrointestinal, respiratory, dermatologic, arthralgia, or myalgia symptoms. The PRO-CTCAE pain score was higher among ECOG PS 2/3 patients. CONCLUSION:In clinical practice, global health was largely comparable to published clinical trials, but PRO-CTCAE items indicated a higher symptom prevalence. Closer monitoring of symptoms is warranted in ECOG PS 2/3 patients.
Cancer immunotherapy experience in the Integral Oncology Centre "Diana Laura Riojas de Colosio", Médica Sur Hospital.
Fernández-Ferreira Ricardo,Motola-Kuba Daniel,Mackinney-Novelo Ileana,Ruiz-Morales José Manuel,Torres-Pérez María Eugenia
Contemporary oncology (Poznan, Poland)
Introduction:The useof immunotherapy in Mexico has been used since 2012 with ipilimumab and since 2015 with nivolumab and pembrolizumab, so it is a matter of necessity to know the experience of these drugs. Material and methods:An observational, descriptive, cross-sectional, and retrospective study was performed in Médica Sur Hospital, where with dossiers from 2012 to June 2018 patients with metastatic cancer who received immunotherapy with ipilimumab, nivolumab, and pembrolizumab for six months were evaluated, searching as principal outcomes the adverse effects of those drugs and as secondary outcomes the response to treatment. Results:Seventy subjects fulfilled the inclusion criteria for the study, and 42 (60%) were women with an average age of 60.73 ±13.64 years (16-82 years). The pathologies that received immunotherapy were the following: melanoma and lung cancer. The most frequent clinical and laboratory adverse effects were as follows: fatigue - 32 (45.71%), asthaenia - 30 (42%), nausea - 8 (11.4%), diarrhoea - 8 (11.4%), and rash - 7 (10%). The worst adverse effects were respiratory and endocrinological: pneumonitis - 10 (14.28%), hypothyroidism - 4 (5.71%), hyperglycaemia - 1 (1.4%), and hypophysitis - 2 (2.9%). With respect to treatment response: complete response - 8 (11.4%), partial response - 11 (15.71%), stable disease - 33 (47.14%), and disease progression - 19 (27.14%). Conclusions:The most common adverse effects did not condition the suspension of treatment or increase in intra-hospital stay, but there were some adverse effects that actually had an impact on evolution, hospital stay, and mortality.
Nivolumab-induced aplastic anemia: A case report and literature review.
Comito Rachel R,Badu Lynette A,Forcello Nicholas
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners
Directed immunotherapy at the programmed cell death-1 receptor has demonstrated efficacy in non-small-cell lung cancer, metastatic melanoma, and various other malignancies. Immune checkpoint inhibitors are innovative therapies producing some impressive clinical responses with a more manageable adverse effect profile when compared to traditional chemotherapy. The more common adverse effects associated with these agents include fatigue, rash, myalgia, pyrexia, and cough, but less common yet serious adverse effects have included immune-mediated colitis, pneumonitis, hepatitis, type 1 diabetes, and encephalitis. Here we present a case of a female patient with glioblastoma multiforme, who was treated with the programmed cell death-1 receptor inhibitor nivolumab and subsequently developed aplastic anemia.
Adoptive immunotherapy combined chemoradiotherapy for non-small-cell lung cancer: a meta-analysis.
Qian Haili,Wang Haijuan,Guan Xiuwen,Yi Zongbi,Ma Fei
The aim of this study was to compare the efficacies between adoptive immunotherapy combined chemoradiotherapy and chemoradiotherapy alone in patients with non-small-cell lung cancer (NSCLC). The databases PubMed, EMBASE, and Cochrane database were searched to identify eligible clinical trials. Data analyses were carried out using a comprehensive meta-analysis program, version 2 software. A total of seven articles were finally included in the analysis. Meta-analyses showed that compared with chemoradiotherapy alone, adoptive immunotherapy combined with chemoradiotherapy could improve the 2-year overall survival [odds ratio (OR)=2.45, 95% confidence interval (CI): 1.60-3.75, P<0.001], but not 2-year progression-free survival (OR=1.81, 95% CI: 0.61-5.36, P=0.284). Specifically, early (OR=3.32, 95% CI: 1.38-7.95, P<0.01) but not advanced (OR=3.75, 95% CI: 0.96-14.68, P=0.057) NSCLC patients were likely to gain a large benefit from the adoptive immunotherapy. Most of the adoptive immunotherapy-induced adverse effects were self-limited, mainly including fever, shiver, nausea, fatigue, etc. and severe toxicities were not observed. Adoptive immunotherapy combined with chemoradiotherapy can delay the recurrence of NSCLC and improve survival in patients, where the benefits are even more significant in patients with early-stage NSCLC.
Lambert-Eaton Myasthenic Syndrome Secondary to Nivolumab and Ipilimumab in a Patient with Small-Cell Lung Cancer.
Agrawal Kavita,Agrawal Nirav
Case reports in neurological medicine
We present a case of a 59-year-old male with a confirmed diagnosis of small-cell lung cancer (SCLC). He had progressive disease even after four cycles of cisplatin and etoposide chemotherapy and 21 cycles of radiation. He was therefore started on immunotherapy with nivolumab every 2 weeks and ipilimumab every 6 weeks. After 4 months of starting immunotherapy, he reported extreme fatigue, muscular weakness, and poor appetite. He was diagnosed with hypothyroidism, primary adrenal insufficiency, and Lambert-Eaton Myasthenic Syndrome (LEMS). LEMS can be both a paraneoplastic syndrome of SCLC and an adverse effect of immunotherapy. Currently, there is no diagnostic test available to determine if a case of LEMS is a paraneoplastic syndrome or immunotherapy-related adverse effect. In our patient, we felt that LEMS was an immunotherapy-related adverse effect rather being a paraneoplastic syndrome. Our determination was based on the time of onset of muscular weakness, presence of other immunotherapy-mediated adverse events, and the appearance of symptoms in spite of SCLC that had been stabilized on immunotherapy. Accordingly, immunotherapy was stopped and a brief tapering course of steroids was initiated. Our patient's muscular weakness from LEMS responded well. His clinical improvement persisted even with radiologic progression of disease after cessation of immunotherapy.
Primary pulmonary leiomyosarcoma -- a case report.
Luthra Munish,Khan Hina,Suhail M Faizul,Avadhani Vaidehi
Archivos de bronconeumologia
Sarcomas are mesenchymal tumors that originate from the stromal elements of the bronchial wall or from interstices of lung parenchyma. Pulmonary sarcomatous neoplasms are a rare and diagnostically challenging group of tumors. They constitute only 0.2%-0.5% of all primary lung malignancies. Primary pulmonary leiomyosarcomas are subdivided into those originating from pulmonary parenchyma, bronchial tree or pulmonary arteries. Here we present a case of 43-year-old African-American female who with chronic cough, fatigue and weight loss. Early detection is the key to the successful management of these patients. The available treatment option is complete resection of tumor. These cases provide an interesting juxtaposition to the management of typical lung cancer.
Nivolumab-induced hypophysitis leading to hypopituitarism and secondary empty sella syndrome in a patient with non-small cell lung cancer.
Chang Jeremy,Tran Jeffrey,Kamel Dina,Basu Arnab
BMJ case reports
We describe the clinical course of a 64-year-old woman with stage IVa lung adenocarcinoma who presented with over 1 month of fatigue, unintentional weight loss and emesis. She initiated treatment with nivolumab immunotherapy 1 year prior and had been tolerating the treatment well. A comprehensive workup revealed multiple endocrinological abnormalities consistent with hypophysitis leading to hypopituitarism in the form of central adrenal insufficiency and hypogonadism as well as a partially empty sella on imaging. This case demonstrates that while receiving novel forms of treatment such as immunotherapy, patients should be monitored closely for a wide range of adverse effects.